The invention relates to a process for agglomeration of a powdery material to obtain spherical granules of a desired narrow granule size distribution with a low intragranular porosity in which the material in a high speed mixer internally coated with a substance to which the materials to be agglomerated and the auxiliary substances required for the agglomeration only have little adhesion, preferably a fluorine-containing polymer, while being mechanically agitated is sprayed with a liquid that is a solution of a binder or a solvent for a binder mixed in the powdery material and then mechanically processed to form and compact granules, which are dried.
Inter alia, in the pharmaceutical industry there is a considerable need for converting powdery drugs or drug-containing mixtures into so-called pellets, i.e. agglomerates, having a uniform granule size with an average diameter between about 1/2 mm and 2 mm. Such pellets are suited for tabletting, as content of capsules and for the preparation of multiple unit doses, i.e. preparations having controlled release rate of the drug, the pellets being provided with a coating for controlling the release rate of the medicament, as described e.g. in U.S. Pat. Nos. 4,718,248 and 4,716,041.
Various methods of converting powders into pellets have been practiced. Thus, use is made of agglomeration in a fluidized bed, or extrusion of the powder after mixing with a binder solution and a finishing treatment of the extrudate with a view to rounding off the particles in a process called spheronization. Plasticizing auxiliary substances are normally added in such methods, e.g. micro-crystalline cellulose in amounts up to about 50%.
With particular respect to the preparation of pellets to be used for medicaments having controlled release rate it is, moreover, desirable to obtain pellets that are more compact, i.e. less porous, than those obtained according to said two prior art methods, thereby allowing tabletting without considerably influencing the release rate from the pellets. In case of high-dosage formulations it is further desirable to pelletize pharmaceutical substances having a drug content in pellets that is greater than the about 60% made possible according to known methods. These types of methods are, moreover, complicated to carry out, since they comprise many process steps and are therefore difficult to transfer to production scale.
In view of the above, great interest attaches to processes of the type recited in the first paragraph of the present specification. Methods of this type are flexible, require only relatively modest investments and make it possible to obtain very compact agglomerates appropriate in the preparation of multiple unit dose formulations having a very large content of active pharmaceutical agent.
A more specific description of agglomeration by using a high speed mixer is to be found in the following literature:
P. Holm: Drug. Dev. Ind. Pharm. 13, 1675-1701, (1987). PA0 H. Gjelstrup Kristensen and T. Schaefer: Drug. Dev. Ind. Pharm. 13, 803 (1987). PA0 T. Schafer, H. H. Bak, A. Jegerskou, A. Kristensen, J. R. Svensson, P. Holm and H. G. Kristensen: Pharm. Ind. 48,9, 1083-1089 (1986) og 49, 3, 297-304 (1987). PA0 T. Schaefer, F. Holm og H. G. Kristensen: Arch Pharm. Chem. Sci. Ed. 14, 1-29, (1986). PA0 H. O. Kristensen, P. Holm and T. Schaefer: Powder Technology 44, 227-287 and 239-247 (1986). PA0 P. Holm, T. Schaefer and H. O. Kristensen: Powder Technology 48, 213-233 (1985). PA0 U.S. Pat. Nos. 4,037,794 og nr. 4,111,371 (both Melliger).
The commercially available high speed mixers used in the agglomeration processes of the type concerned are round-bottomed or flat-bottomed bowls with a mixer device, designated impeller or mixing blade, rotating about a central shaft close to the bottom and which possibly also follows the lower portion of the lateral walls of the bowl. Most commercial bowls include, moreover, a so-called chopper consisting of some, very fast rotating arms or knives, typically inserted through the lateral wall or the cover of the mixer bowl. The bowl is also provided with means for supplying a binder solution, e.g. in the form of a nozzle accommodated in the bowl cover and intended to spray an atomized solution on a smaller area of the powder mass moving in the apparatus during the operation thereof.
Some of the commercially accessible high speed mixers for carrying out agglomeration operations are intended to provide a moist granulate necessitating drying in a fluidized bed, in a micro-wave drier or on drier trays, while others, e.g. those disclosed in the above two referenced US patents, make it possible to dry the material during processing by flowing drying air through the mixer bowl.
Even though methods of agglomeration by use of a high speed mixer may, as stated, entail advantages in comparison with other methods of granulation they suffer, however, from the drawback that it has not so far been possible to accomplish them so as to obtain in a reproducible manner, a high yield of fractions with a desired granule size distribution. Particularly, the preparation of multiple unit dose formulations requires a very narrow granule size distribution and particles which do not fall within the fixed limits of granule size must be strained off and discarded or fed back, possibly after grinding.
The first one of the above references (P. Holm) suggests covering the wall of the mixer bowl with polytetrafluoroethylene to obtain more uniform results, but high speed mixers with such a coating have not been used industrially.